Diagnosis and management of vulvodynia in postmenopausal women

Maturitas 108 (2018) 84–94

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Review

Diagnosis and management of vulvodynia in postmenopausal women a

b,c

d

T

e

Pedro Vieira-Baptista , Gilbert Donders , Lynnette Margesson , Libby Edwards , ⁎ Hope K. Haefnerf, Faustino R. Pérez-Lópezg, a

Lower Genital Tract Unit, Centro Hospitalar de São João, Porto, Portugal Department of Obstetrics and Gynecology, Antwerp University Hospital, Antwerp, Belgium Femicare, Clinical Research for Women, Tienen, Belgium d Department of Obstetrics & Gynecology and Surgery (Dermatology) Geisel School of Medicine at Dartmouth, NH, USA e Mid-Charlotte Dermatology and Research, Charlotte, NC, USA f Department of Obstetrics and Gynecology, Michigan Medicine, Ann Arbor, MI, USA g Department of Obstetrics and Gynecology, Hospital Universitario Lozano-Blesa, University of Zaragoza Faculty of Medicine, Zaragoza, Spain b c

A R T I C L E I N F O

A B S T R A C T

Keywords: Bladder pain syndrome Clitorodynia Menopause Vestibulodynia Vulvar pain Vulvodynia Vulvovaginal atrophy

Vulvodynia, defined as vulvar pain or burning sensation for more than 3 months, without an identifiable cause, can occur at any age. In this paper, the authors address the classification, epidemiology, etiology, diagnosis, and treatment of this condition, focusing on postmenopausal women. In postmenopausal women, vulvar pain and dyspareunia can often be attributed to low levels of estrogen resulting in vulvovaginal atrophy. While correction of vulvovaginal atrophy is an important part of the management of these patients, it will usually be insufficient to manage vulvodynia. The treatment of vulvodynia includes general care measures, topical, oral, or injectable agents, psychological approaches, pelvic floor rehabilitation and, in some cases, surgery. No particular intervention has been shown to be superior, so a “trial and error” strategy is usually used.

1. Introduction Vulvodynia is a common condition. Despite having been first described in the 19th century, is still not widely acknowledged [1,2]. Many providers are unaware of this condition, missing opportunities to help these women who have a substantially impaired sexual life and quality of life in general [3]. The diagnosis is one of exclusion. Before it can be assumed, other significant vulvar, vaginal, urological, and musculoskeletal pathology must be excluded. However, the diagnosis and management of vulvodynia are often neglected. Both can be more challenging in postmenopausal women, among whom vulvar dermatoses (e.g. lichen sclerosus) and estrogen deprivation are common and the symptoms of these can resemble and overlap those of vulvodynia [4,5]. Vulvodynia often is assumed to be “psychological” or “psychosomatic”, or “vaginismus” in younger women, while it is often considered to be a consequence of low estrogen levels or vulvovaginal atrophy in the older population. Even though psychological factors often are involved, they do not seem to be the main explanation for the patients’ symptoms [6,7]. Vulvodynia is a significant cause of dyspareunia; however the symptoms can be present even in the absence of intercourse [8]. In this paper, we review the approach to the diagnosis and

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management of vulvodynia, paying special attention to the particular aspects of the disease in older women. 2. Methods A thorough literature search was performed using Pubmed to identify the most relevant papers and guidelines in the field. The terms “vulvodynia” or “vestibulodynia” were initially searched. These terms were also combined with “menopause”. 3. Definition and classification of vulvodynia The term “vulvodynia” was defined by the International Society for the Study of Vulvovaginal Disease (ISSVD) as “vulvar discomfort, most often described as burning pain, occurring in the absence of relevant visible findings or a specific, clinically identifiable, neurologic disorder” [9] − in practical terms, idiopathic vulvar pain, related or not related to sexual activity. In 2015, the definition and classification of vulvodynia were revised by the ISSVD, along with representation from the International Society for the Study of Women's Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS). Vulvodynia is now defined as “vulvar pain of at least 3 months' duration, without a

Corresponding author at: University of Zaragoza Faculty of Medicine, Zaragoza 50009, Spain. E-mail address: [email protected] (F.R. Pérez-López).

https://doi.org/10.1016/j.maturitas.2017.11.003 Received 8 October 2017; Received in revised form 25 October 2017; Accepted 1 November 2017 0378-5122/ © 2017 Elsevier B.V. All rights reserved.

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the etiology and pathophysiology of localized rather than generalized vulvodynia, even though it remains unknown whether or not these are manifestations of the same entity [23]. Leclair et al. demonstrated that pre and postmenopausal women with vestibulodynia share histologic features of neurogenic inflammation, however these are much more pronounced in the latter [24]. A chronic neurogenic inflammation, possibly elicited by mast cell degranulation [25], is commonly found in biopsies and vestibulectomy specimens. The inflammatory process includes mast cell recruitment (also known to happen in other pain syndromes, such as fibromyalgia and bladder pain syndrome [BPS]), submucosal nerve growth (with superficial nerve endings), increased numbers of CD4-positive T cells, and sometimes plasma cells in the epithelium [25–28]. However, agreement in the literature is lacking. For example, a recent study by Papoutsis et al. found no association with mast cells in patients with vulvodynia [29]. The vestibule has its own localized immune system which Tommola et al. designated “vestibule-associated lymphoid tissue” (VALT) [27]. Several inflammatory or infectious processes, such as candidosis, may, in theory, trigger the inflammatory response by VALT. The immunological response to these processes may be heightened in women with vulvodynia [22,30]. Although a substantial number of vulvodynia patients recall a history of candidosis, most often it was a diagnosis based only on symptoms, without further laboratory confirmation, thus making it unreliable [31,32]. Nevertheless, Ventolini et al. have shown that there is a specific immunological response after exposure to Candida in patients with vulvodynia, and, accordingly, postulated that this can be the first insult that later leads to pain [33]. Foster et al. demonstrated that this response is different in women with and without vulvodynia [30]. Nevertheless, treatment with antifungals generally will not have an impact in vulvodynia patients − Candida can represent the initial insult, but does not have to be present in the following stages of the disease. The role of the vaginal microbiome is still poorly known, but Ventolini found L. crispatus to be absent in women with vulvodynia, in contrast to L. gasseri, which was found only in those with past or previous vulvodynia [33]. Donders et al. correlated aerobic vaginitis (AV) with the severity of disease (more painful loci and more intense pain in patients with AV than in those without AV) [34]. A role for genetics with vulvodynia can be presumed by the increased incidence of vestibulectomy within women of the same family [26]. However, it must be taken into account that this can be biased, by, for instance, access to the same health care providers. As in other chronic pain syndromes, several genetic polymorphisms that increase the susceptibility to vulvodynia have been described [35]. These include polymorphisms in the gene coding for the interleukin 1 receptor antagonist [36], mannose binding lectin [37,38], and in the serotonin receptor gene (5HT-2A) [39]. In women taking oral contraceptives, polymorphisms of the guanosine triphosphate cyclohydrolase gene [40] and longer cytosine-adenine-guanine trinucleotide repeats in the androgen receptor coding gene were also identified [41]. Generalized vulvodynia is a form of complex regional pain syndrome, often associated with other pain syndromes (fibromyalgia, BPS) and an increased perception of systemic pain. This process is more likely due to central nervous system sensitization than to local factors [42–44]. Other factors possibly associated with vulvodynia are embryologic and/or related to early fetal development (the endodermal origin of the vestibule [45], which could explain the common association with the BPS) [46], dietary (however, the role of oxalates has been challenged recently) [47–49], sexual (sexual abuse, age of sexual debut) [50,51], and heightened pelvic muscle tone [52]. The role of hormones is controversial: several studies associate the use of oral contraceptives and a hypoestrogenic state with the development of vulvodynia [53,54], but others have not found this association [55].

clear identifiable cause, which may have potential associated factors” [10]. Additionally, it was highlighted that women with specific vulvar disorders (e.g. vulvar dermatoses) are not necessarily excluded from having vulvodynia. Several descriptors can be used to classify or characterize vulvodynia, according to:

• Location: localized (e.g., vestibulodynia, clitorodynia), generalized • • •

(the majority of the vulva is affected) or mixed (presence of both localized and generalized pain or burning). Need for a stimulus to elicit the symptoms: provoked (the symptoms are elicited by a stimulus, such as intercourse, touch, bicycle seats or saddles, tight clothes), spontaneous (the symptoms occur in the absence of a stimulus) or mixed (provoked and spontaneous symptoms in the same woman). Onset: primary (the symptoms were always present − since the first attempt at intercourse, tampon use or, in generalized vulvodynia, the symptoms were always present) or secondary (symptoms were present at some point in life, but not previous to that). Temporal pattern: persistent (any pain that lasts for 3 or more months − which can be divided into “constant” or “intermittent”), immediate (symptoms start during the exposure to the provoking stimulus) or delayed (symptoms start after the provoking stimulus).

An addendum to the vulvodynia classification, clarifying the descriptors of vulvodynia is expected to be published during the next few months. There is some controversy over whether vulvodynia should be classified as a “sexual dysfunction” − it may be more accurate to consider it a chronic dysfunctional (rather than neuropathic) pain [11]. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition, the “genitopelvic pain/penetration disorder” encompasses vaginismus and dyspareunia. In this document, vulvodynia is never referred as a main cause of dyspareunia; failure to diagnose it can lead to inadequate treatments [12,13]. 4. Epidemiology Vulvodynia has been described in every age group [14–16]. Its prevalence has been found to range between 6.1% and 20.8%, but most of the data relate to premenopausal women [2,14,17]. In an European study, the prevalence of vulvodynia dropped after the age of 60 [2]; in a study from the United States, considering only sexually active women, the prevalence was stable up to 70 years of age [16]. More recently, Mitro et al. found a prevalence of 4.0% of vulvodynia in postmenopausal women, although a significant number reported that the symptoms had started before the onset of menopause [17]. The lower prevalence found in the later study may be explained by ethnic factors, as it included a significant proportion of black women, who typically have lower incidences of vulvodynia [18]. The lower incidence in black women may be not real, but attributable to cultural factors (i.e. black women are more likely to consider pain as aching) [19]. Generalized vulvodynia seems to be more common in older women, while localized vulvodynia prevails in younger women [20]. Despite the apparently lower prevalence of vulvodynia in postmenopausal women, these are often very severe cases, and can be difficult to deal with [21]. 5. Etiology, risk factors, and associations Vulvodynia is multifactorial in origin; the precise causes are still being investigated. The etiology includes combinations of pelvic floor abnormalities, dysfunctional/neuropathic pain (including central processing disorders, peripheral neuropathy, and complex regional pain syndromes), increased numbers of cutaneous nerve fibers, low-grade inflammation, psychological factors (anxiety, depression), and genetic predisposition (Table 1) [22]. Most theories and studies have addressed 85

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Table 1 Risk factors and associations with vulvodynia. Factors and associations Embryonic Hormonal Genetic

Neurological (local) Neurological (central)

Musculo-skeletal and myofascial Inflammatory and infectious

Vaginal flora/microbiome

Allergic Psychosocial, relational and psychological

Examples -

-

Comments

Frequent association with BPS Lower threshold of pain at the umbilical scar Oral contraceptives Increased risk of vestibulectomy within the same families Genetic polymorphisms (interleukin 1 receptor antagonist mannose binding lectin, serotonin receptor gene, guanosine triphosphate cyclohydrolase, and longer cytosine-adenine-guanine trinucleotide) Neurogenic inflammation BPS Fibromyalgia Irritable bowel syndrome Glossodynia Temporo-mandibular joint pain Coxofemoral joint pain Increased pelvic floor tonus Postural defects Scoliosis Urinary tract infections Candidosis Herpes Trichomoniasis Lactobacillus gasseri Cytolytic vaginosis Aerobic vaginitis/DIV IgE anti-seminal fluid Reduced desire and excitation Orgasmic dysfunction Reduced self esteem (sexual and image) Global psychological distress Depression Anxiety Physical/sexual abuse

Structures with the same embryonic origin (urogenital sinus)

Polymorphisms associated with increased risk of infection, exacerbated inflammatory response, and susceptibility of developing vulvodynia while taking oral contraceptives Controversial

Can be a secondary phenomenon, but must addressed in all patients

Difficult to establish relations, as it is dependent on patient’s recall and usually there is no laboratorial confirmation of the episodes

Further studies needed to confirm possible associations

Not always easy to set a frontier on whether the associations are causal or consequent

BPS: bladder pain syndrome; DIV: desquamative inflammatory vaginitis.

utmost importance. It is not uncommon to find women who have been subjected to laser treatments or other vulvar surgical procedures to treat the symptoms, even though a correct diagnosis was not attained. Exploring associated conditions, especially other pain syndromes (e.g. fibromyalgia, BPS, irritable bowel syndrome, glossodynia, etc.), is an important part of clinical evaluation (Table 1). Women with BPS are commonly unaware of the condition, thus the importance of exploring voiding habits and referral to an urologist with expertise in this field. This detailed history must include previous diagnoses and diagnostic tests, as well as previous treatments (including alternative therapies) and their results. It is also important to enquire about any history of trauma and surgical interventions (especially those involving the spine, abdomen or pelvis). History of urinary incontinence is also important, as the continuous exposure of the vulvar skin to urine and pads is an additional irritating factor, which usually exacerbates other conditions [58]. After permission is obtained, psychological and sexual history must be evaluated in detail. For instance, the impact of vulvodynia on sexual activity can be a useful tool to monitor the response to treatment (for example, from unable to have intercourse to being able to have intercourse). The use of validated questionnaires, such as the Female Sexual Function Index (FSFI) [59], makes this evaluation objective.

6. Diagnostic approach The diagnosis of vulvodynia in postmenopausal women, as in premenopausal women, is one of exclusion. Treating vulvodynia patients implies trust between the health care provider and the patient, which can take time to build [56]. It is common that the patient has seen several other health care providers prior to presentation to your clinic [14], with a high chance that some considered it just a “psychological” issue or a “sexuality disorder”. Sometimes, the full evaluation of the patient cannot be completed in just one session. The health care provider must be prepared to take a full medical, psychological, and sexual history, as well as to evaluate the pelvic floor. Vaginal atrophy is a common finding in these women; however, even in its presence, it cannot be assumed that it is the sole cause of dyspareunia or vulvar pain [21]. The diagnostic approach aims mostly at the exclusion of other causes for the burning sensation or pain.

6.1. Clinical history A thorough clinical history is mandatory for the diagnosis and can lead to a high suspicion of vulvodynia. Interestingly, self-reported symptoms alone are quite accurate for the diagnosis of vulvodynia [57]. A significant number of women will complain of “burning” rather than “pain” as their main symptom. It is mandatory to characterize the pain or burning and their duration, for further classification. While still menstruating, sensations of burning fluctuating over the menstrual cycle can lead to alternative diagnoses, such as non-albicans candidosis or cytolytic vaginosis. Provoking factors must be explored (tampon use, touch, sitting, bicycle riding, etc.). Knowledge of previous gynecological/pelvic interventions is of

6.2. Physical examination Physical examination should not be limited to the pelvic organs. It should start with a general examination, evaluation of posture (some abnormalities can be noted with the patient still sitting), body asymmetries and, especially, scoliosis [2]. Vestibular erythema (seen around the ostia of Bartholin and Skene's glands) is not required for a diagnosis of vulvodynia [60]. More recently, the definition was changed in order not to exclude women with 86

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lactobacillary grades [72]. Microscopy is an excellent tool to evaluate the presence of vaginal atrophy − if present, intermediate and parabasal cells (and sometimes even basal cells) will dominate: smaller, round cells, with a large nucleus. Vaginal discharge can be collected using a gloved finger, a spatula, a cervical brush or, less ideally, a cotton swab (as it can leave fibers in the smear). The sample can easily be collected without introducing a speculum. Attempts should be made to avoid touching the cervix. Several abnormalities detected by microscopy can play a role in the differential diagnosis of vulvar pain, such as the presence of cytolytic vaginosis, aerobic vaginitis, Candida or Trichomonas vaginalis.

other vulvovaginal conditions [61]. The pelvic examination should be done gently and slowly, and the health care provider should explain every step beforehand, in order to gain the patient’s confidence and make her feel comfortable. Vulvar inspections must include detailed examination, looking for vulvar anatomical abnormalities, rashes, tumors, or other skin changes. Speculum examination can be postponed to one of the following visits if it is too painful [62]. If the use of a speculum is deemed necessary, a small one should be used. It is common for women to recall this part of the exam as extremely painful and traumatizing. In cases where the tension associated with the idea of a vaginal digital examination is very high, the same strategy can be used. Using one finger instead of two significantly reduces the discomfort, and should be routine in these women. During vaginal examination (digital, with speculum or using a swab), effort must be made to avoid touching the vestibule and the hymen, to minimize pain and discomfort. Full assessment of the pelvic floor muscles is mandatory, as an increase in their tone, as well as diminished strength and control are common findings [52]. Assessment includes noting areas of tenderness, trigger points, or muscular tension [63]. The pudendal nerve pathway can also be palpated and tested for pain [64]. Palpation of the bladder and urethra, uterus/ovaries, and a rectovaginal examination completes the pelvic examination.

6.6. pH The measurement of pH is an indirect evaluation of the lactobacillary status of the woman: in cases of dysbiosis [73], the bacterial dominance will shift from lactobacilli to other anaerobes (bacterial vaginosis) or to aerobes (aerobic vaginitis) [74], with a subsequent increase in pH. However, a normal or lowered pH is found in cases of cytolytc vaginosis and in most cases of candidosis. Also, an abnormal pH will not distinguish between the different types of dysbiosis, trichomoniasis, atrophy or even candidosis. It can be a useful complement in postmenopausal women who have started hormonal therapy (local or systemic) [75].

6.3. Q-tip test (QTT) or cotton swab test

6.7. Other tests

The cotton swab test is the mainstay in the diagnosis of vulvodynia [60]. It consists of using a Q-tip to test whether there is pain in the perineum and vulvar structures, upon light touch (allodynia). It starts from the inner aspects of the thighs, moving medially and symmetrically. It is best initially to avoid testing the most painful areas, so that the patient can become more relaxed. The focus should be on the vestibule and the hymeneal ring. The patient usually is asked to rate the pain on a scale of 0 (no pain) to 10 (most severe pain ever). Alternatively, pain can be classified as mild, moderate or severe [23]. This simple test allows classification of vulvodynia as localized or generalized. It is a useful tool, not only in the diagnosis of vulvodynia, but also in follow-up testing. Nonetheless, it is subjective and “false positives” are possible. A cotton swab test score does not need to be 0 in order to be “normal” [8]. More sophisticated techniques (e.g. von Frey filaments or vulvoalgisiometers) to map and grade the pain do not seem to perform much better than the QTT in clinical practice [65,66]. Foster et al. have suggested the use of the “tampon test”, consisting on the introduction of a tampon, as a surrogate for pain during intercourse, and scoring the pain on a scale of 0–10 [67,68]. We consider, however, that postmenopausal women may not always be willing to undergo this test.

Exclusion of the presence of T. vaginalis can be advisable. As the performance of wet mount microscopy is lower than desirable for the exclusion of this parasite, polymerase chain reaction (PCR) is the best option [76]. Specific T. vaginalis cultures are not so readily available and it takes longer to get the results. 6.8. What not to do There is no evidence that the use of a colposcope (to magnify the vulvar structures), acetic acid, toluidine blue, or testing for human papillomavirus are useful [23,60,77,78] in this population. In case of doubt, a magnifying lens to observe the vulva should be enough. Even though in one series up to a quarter of vulvodynia patients were subject to a vulvar biopsy at some point [79], it is of little interest in the diagnosis of vulvodynia, given the absence of specific histological findings [80]. Isolated vulvar erythema should not prompt a biopsy. However, it has been argued that a vulvar biopsy can sometimes lead to the diagnosis of a previous unsuspected vulvar dermatologic condition [81]. There is no indication to evaluate serum levels of sexual hormones.

6.4. Cultures 6.9. What to do Cultures for Candida, but not sensitivity testing, are recommended as part of the diagnostic assessment of vulvodynia [60]. Patients testing positive for Candida should be treated appropriately. Cultures, however, cannot distinguish between colonization and infection or establish that the symptoms are attributable to a specific microbial agent. For this reason, cultures for bacteria are not recommended [69].

As stated above, clinical history is probably the single most important part of the patient’s evaluation − in most cases in which vulvodynia is suspected, it usually will be confirmed. Interestingly, according to our experience, when a patient considers she has vulvodynia, she usually is correct. The evaluation proposed above is what should be done under ideal circumstances. However, lack of access to microscopy, cultures, or PCR techniques should not preclude starting treatment if the suspicion is present [82].

6.5. Microscopy Vaginal flora microscopy is a fundamental step in the evaluation of vulvodynia patients. A vaginal sample can be collected and sent to the laboratory for Gram staining or, preferably, used for direct wet mount microscopy (ideally using phase contrast) [70]. The latter can be performed in a matter of a few minutes, is easy and cheap, and can be mastered with minimum training [71]. Additionally, it can perform even better than Gram staining, especially in the evaluation of the

7. Differential diagnosis It must be established whether persistent vulvar pain is attributable to a specific cause; otherwise, it is a vulvodynia [61] (Table 2). The diagnosis can frequently be suspected from the clinical history. 87

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Table 2 Causes of vulvar pain to be considered in the postmenopausal patient. CAUSES Infectious Herpes genitalis

• • Herpes zoster

• Candidosis (possibly non-albicans) • Trichomoniasis papilloma virus (warts, vulvar high grade squamous • Human intraepithelial lesion) Hormonal Vaginal atrophy

•

Dermatological Lichen sclerosus

•

• Lichen planus • Irritant contact dermatitis • Hidradenitis suppurativa grade squamous intraepithelial lesions (HSIL) previously termed • High vulvar intraepithelial neoplasia (VIN) Neurological Pudendal neuralgia

•

Other Cytolytic vaginosis

•

• Aerobic vaginitis (AV)/desquamative inflammatory vaginitis (DIV) • Vulvar cancer • Interstitial cystitis/bladder pain syndrome

COMMENTS

-

Frequently recurrent, localized, with associated lesions (blisters, erosions, ulcers). PCR (or cultures) useful for the diagnosis. Unilateral blisters, limited to one dermatome. Post-herpetic neuralgia can follow a crisis. Often seen in immunosuppressed patients. PCR (or cultures) useful for the diagnosis. Vulvovaginal signs can be discrete. Non-albicans candidosis usually more associated with burning, rather that itching. Diagnosis made with wet mount microscopy or cultures. Intensity of symptoms can be very variable. Frequently associated with bacterial vaginosis and vaginal discharge. Diagnosis made by wet mount microscopy or PCR. Treatment of partners mandatory. Warts usually with typical papillae. If pigmented, atypical or in immunosuppressed patients, consider biopsy.

- Easily accessed by clinical examination (vaginal mucosa pale, absent rugae, vestibular retraction). - Wet mount and pH evaluation allow objective evaluation of atrophy and monitoring of the response to estrogen treatment. - Distortion of the vulvar anatomy (atrophy of the labia minora, phimosis, lichenification of the vulvar structures medial to the inner side of the labia majora). - Diagnosis usually clinical, although biopsy if suspicious for precancer or cancer. - Usually with a good response to ultrapotent topical steroids. - Distortion of the vulvar anatomy similar to what is find in lichen sclerosus, but frequently more reddish, with erosions. - Common involvement of other mucosae (vagina, mouth, etc.). - Diagnosis usually clinical, although biopsy if suspicious for precancer or cancer. - Frequently responds to ultrapotent topical steroids. - Skin injured by environmental factors (soaps, detergents, perfumes, etc.) - Lesions confined to the place of contact with the irritant. - Good response to avoidance of irritating stimulus and ultrapotent topical steroids. - The diagnosis is usually straightforward (abscesses, sinuses, and fistulae). - Positive family history is common. - Lesions can be present in other locations (submammary sulci, armpits). - No typical presentation (can be white, red, or brown). - Any suspicious lesion must prompt a biopsy. - Vulvar pain with variable extension, uni or bilateral. - Worsening with sitting. - Often have a history of pelvic trauma or bike riding. - If symptomatic, the usual symptom is burning. - The diagnosis is easily made by wet mount microscopy (bare nuclei, increased number of lactobacilli). - Good response to sodium bicarbonate irrigations. - Fluctuating severity of symptoms, usually long standing. - Usually associated with vaginal discharge with foul smell. - DIV is the severe form of AV. - Diagnosis made by wet mount microscopy (lack of lactobacilli, inflammation, atrophy, presence of cocci or bacilli). - Responds variably to topical steroids, estrogen and antiseptics/antibiotics. - Can present as ulcerations or tumors. - In case of suspicion, biopsy is mandatory. - Frequently associated with vulvodynia. - Patients have frequent voiding, including nocturia and pain, partially relieved with micturition.

floor muscle tightness and anxiety. If one day the exact cause(s) of vulvodynia can be established, more specific, efficacious treatments are likely to be forthcoming. In the future, genetic profiling may be advantageous [83]. Even though several high-quality guidelines concerning vulvodynia exist [60,77,84], there is a lack of good evidence supporting most of the treatments used in this field. Few studies have used a control/placebo group, been double blinded, had long-term follow-up and used validated scales [85,86]. The placebo effect in vulvodynia treatments cannot be ignored, since as many as 40–50% of patients record a 50% reduction in score on a pain scale [68,85,87]. Most studies have addressed localized vulvodynia specifically and several authors failed to

The list of differential diagnoses is long. In the presence of another diagnosis, even if not very likely to be the cause of pain, that condition must be treated before vulvodynia can be assumed. 8. Treatment A variety of treatments have been utilized for vulvodynia (Table 3). Given that the etiologies and the mechanisms leading to vulvodynia are poorly understood, most treatments are empirical and have limited success. However, many patients gain much improvement, even though they do not completely clear their symptoms. Some patients experience ongoing exacerbations that are controllable with management of pelvic 88

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Table 3 Management of vulvodynia. Adapted from Edwards L and Lynch PJ [128] General, nonspecific measures

Pelvic floor evaluation and physiotherapy

Neuropathic pain/pain syndrome, oral medication

Counseling

Vestibulectomy Other therapies

- Patient education, handouts - Counseling for most - Evaluation for and correction of coincidental abnormalities; irritant contact dermatitis, estrogen deficiency, infections, etc. - Topical lidocaine 2% jelly, 5% ointment (variable burning with application) - Manual therapy techniques, - Pelvic floor muscle and girdle education - Biofeedback - Transcutaneous electrical nerve stimulation (TENS) - Peripheral and central nervous system desensitization strategies - Home exercise programs Antidepressant class medication: - Tricyclic medications beginning at 5–10 mg, titrating as high as 150 mg hs - Duloxetine, beginning at 20 mg titrating up to 60 mg/d. - Venlafaxine sustained/extended release, beginning at 37.5 mg, titrating up to 150 mg q.d. Anticonvulsants class medication: - Gabapentin beginning at 100 mg, titrating as high as 1200 mg t.i.d. - Pregabalin beginning at 25 mg, titrating as high as 300 mg b.i.d. - Other options: topiramate, lamotrigine - Cognitive behavioral therapy - Psychological counseling - Sex therapy - Antidepressant therapy/SSRIs Consider only in women with vestibulodynia (pain strictly localized to the vestibule) Topical therapies - Lidocaine 5% ointment at introitus under occlusions hs - Estradiol cream at introitus under occlusion hs - Amitriptyline 2%/baclofen 2% compounded - Amitriptyline 2%/baclofen 2%/ketamine 2% compounded - Nitroglycerin 0.2% compounded, three times a week and 5–10 min before sexual activity - Gabapentin compounded - Diazepam 10 mg vaginal suppositories Other options: botulinum toxin, hypnotherapy, acupuncture used for vulvodynia by some

SSRI: selective serotonin reuptake inhibitors; hs: hora somni (bed time).

vagina) has shown to improve or cure dyspareunia in more than 80% of postmenopausal women [92]. The response to estrogens can easily be monitored using wet mount microscopy or pH evaluation. Only a third of postmenopausal women with vulvar symptoms are prescribed estrogen replacement therapy (oral or vaginal). Among those to whom it is prescribed, more than half will not respond. This may be secondary to: vulvar rather than vaginal application of topical estrogens, or to non-use due to fear of cancer or cost, or to simply forgetting to use the treatment [93]. It is important to inform the patient that it is normal to feel burning during the first few weeks after starting the application of topical estrogen (lower pH and more abundant discharge). Some will consider creams “messy” and, in these, considering other formulations can be useful. Recently, despite the absence of high-quality evidence of its efficacy and safety, vaginal laser is being recommended to treat vaginal atrophy and even vulvodynia itself. Such techniques are contraindicated in vulvodynia patients [94,95]. On the other hand, even in women on anti-estrogenic therapy for breast cancer, topical use of ultralow dose of estriol can be safely considered [96], which is also proven to be an efficient treatment of vulvovaginal atrophy during menopause [97]. Vulvodynia patients must be taught to minimize the application of unnecessary products in the genital area and to limit the frequency of washing − this may include stopping the use of soaps, intimate hygiene products, etc. in order to minimize the risk of irritant/contact dermatitis, which will worsen symptoms. Washing of the genital area should be limited to no more than twice a day, preferably using only warm water. Some women will find relief using cool gel packs [60]. Women should also be advised not to use panty liners and to wear loose underwear, made of natural fabrics (cotton or silk), in order to minimize trauma. Not wearing underpants during the night is also advisable [60]. Liberal use of emollients is advisable. Whenever topical medication is needed, ointment formulations are preferable to creams, due to a

distinguish between localized and generalized subtypes. However, the need to distinguish between localized and generalized is debatable. The characteristics of women with generalized vulvar dysesthesia are similar to those of women with localized pain, supporting the theory that the 2 disorders may represent 2 presentations on a continuum of severity rather than 2 distinct entities [88].

8.1. General measures Some women will find a great relief just by the simple fact that a proper physical diagnosis is obtained (“to give the disease a name”). These women are commonly considered to have psychological or psychiatric disease, to complain of pain in order to avoid sex, or to be overreacting, all of which can be very disturbing to the patient [89]. The therapeutic options must be discussed in a realistic way. Patients need to be informed that a treatment may not work, and given the available options in case of failure of a certain therapy (“trial and error approach”). Patients need to know that the process may be lengthy, with ups and downs, and progress slowly [23,86,90]. In terms of outcomes, it is more realistic to tell patients that the goal is to achieve a significant improvement in pain relief, sex life and general quality of life, rather than promising complete and definitive cure [62]. Ideally, vulvodynia patients should be managed by multidisciplinary teams; prompt referral to specialized centers can lead to better results [91]. However, these clinics are not widely available and this should not preclude or delay treatment of the patient. Any identified conditions (dermatoses, infections), even if considered unlikely to be the cause of the symptoms, must be corrected prior to any other approach being tried. Specifically when treating postmenopausal women with signs of atrophy, vaginal and/or systemic estrogen replacement is advisable. The use of topical estrogen in the vestibule (rather than just in the 89

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the main one for which they are usually prescribed, and that studies have demonstrated their effect on neuropathic pain [105]. Patients must be advised that the expected effect can take several weeks to appear (sometimes up to 12 weeks), in contrast to secondary effects, which tend to be common from the beginning but wane with continued use [60,77,106]. Time to response may be proportional to the duration of symptoms [106–108]. Moderation in alcohol consumption is advisable during treatment (one drink a day) [60]. As there are no studies comparing these two classes of medication, the choice to start one or the other will be based in personal experience, associated conditions and secondary effects. The use of medication from the antidepressants class can have a dual effect: in pain and in the treatment of depression, which commonly is superimposed in these patients [109]. Tricyclic medications, especially amitriptyline, are the most commonly used medications for vulvar pain; however, caution is advised with elderly patients. In patients over 75–80 years of age, management with anticonvulsants is often recommended. Dosages needed for the treatment of pain are usually lower than for the treatment of depression. While the medications are usually started with dosages of 5–25 mg/day, taken 2 h before bedtime, in the elderly they should be started at lower dosages (5–10 mg), and increased as needed, at a rate of 10 mg/week. Maximum dosage should not exceed 150 mg/ day (patients often require lower dosages) and suddenly stopping the treatment is not advised. The use of these medications is not recommended in women with cardiac conditions or those taking monoamine oxidase inhibitors [60]. Secondary effects include dry mouth, constipation, somnolence, weight gain, and palpitations. These are some of the few drugs to have shown efficacy in generalized vulvodynia (47% of women have a full response and an additional 43% see more than 50% improvement) [107]. For other tricyclic medications (desipramine, nortriptiline) and other classes, such as selective serotonin re-uptake inhibitors and selective norepinephrine re-uptake inhibitors, there is either a lack of evidence or the evidence does not support their use [85,90,110]. However, the use of venlafaxine and duloxetine can be considered in older patients, as they have a less sedating effect. In women with stress urinary incontinence duloxetine can reduce urine leakage. Caution must be taken, however, as it has been related to mental health problems and suicidality [111]. Gabapentin and pregabalin are the most commonly tried anticonvulsants for vulvodynia. These drugs are most suitable for use in women with pelvic floor dysfunction [90,106]. There is far more experience and evidence on its use in the treatment of other neuropathic pain conditions. In an observational study of 152 patients with vulvodynia, the use of gabapentin led to resolution of at least 80% of the symptoms in 64% of participants [108]. Gabapentin should be started at low doses and then gradually increased. While dose increments of 300 mg are often recommended, in the elderly population 100 mg increments are utilized with a gradual increase (generally weekly). While patients are instructed not to exceed 1200 mg by mouth three times a day, in the elderly population this dose is often not required or recommended. It is increased according to the patient’s needs and tolerance. These drugs are reported to be better tolerated than tricyclic antidepressants and do not have significant interactions with other drugs. The most common adverse effects include dizziness, somnolence, fatigue, headache, loss of concentration, and blurred vision [112]. However, tolerance to these drugs is reduced in older people, with increased risk of balance problems and cognitive impairment [77]. Pregabalin can be used instead of gabapentin; however, its price can limit its use. It would be of interest to test whether combining lower doses of these two classes of medication (tricyclic antidepressants and anticonvulsants) can improve outcomes and reduce the adverse effects.

lower risk of sensitization [60]. Lubricants should be recommended for sexual intercourse; some women, however, will report increased burning with the use of some of these products [98]. If urinary incontinence is present, all efforts must be made to correct or minimize it, thus limiting the irritation of the vulvar skin by urine and/or pads. Referral to a female pelvic medicine and reconstructive surgeon (urogynecologist) can be advisable if the health care provider is not used to treating urinary incontinence. The recommendation for the use of emollients, such as plain petrolatum used in a thin film, must be considered in these patients. 8.2. Topical medication The use of topical lidocaine (2–5%), in the form of jelly or ointment, is recommended in several guidelines and is, probably, the most commonly used initial treatment approach in vulvodynia, both as extended overnight use or, as needed, prior to sexual intercourse [99]. It has been postulated that its anesthetic effect can act on nociceptor proliferation and sensitization, reducing its hyperexcitability. The study results, however, are contradictory: while Zolnoun et al. [100] demonstrated an increase in the ability to have intercourse from 36% to 76%, Foster et al. [68] found no difference compared with placebo, in a randomized controlled trial. Furthermore, in the former study, the likelihood of response was lower in women with BPS − most likely representing a lower chance of response in generalized vulvodynia. It has to be kept in mind that there also is a small risk of sensitization to lidocaine. Benzocaine is never recommended, as it is a major irritant and a topical allergen [101]. It is common that women report burning or stinging for some minutes after the application of lidocaine and should be warned and reassured about this [101]. When prescribing lidocaine, women or couples must be informed that a male partner can also feel numbness of the penis, and that oral contact with the anesthetic should be avoided. The available data do not allow a high-grade recommendation for the use of lidocaine. Several other topical agents have been tried (clobetasol, cromolyn, montelukaste, nifedipine, capsaicin, doxepine, nitroglycerine, antifungals, etc.), sometimes with anecdotal reports of success. However, scientific evidence either is against or does not support their use [85,90]. Several of these treatments have to be prepared by pharmacists and have the potential to additionally irritate the vulva. Topical gabapentin (2–6%), in a retrospective observational study, afforded significant improvement of pain scores and ability to have intercourse, in both women with localized and women with generalized vulvodynia [102]. Amitriptyline 2% associated with baclofen 2% compounded in a cream in a retrospective study gave a 71% response rate in women with refractory symptoms, but had significant side-effects [103]. Since topical medications have minimal absorption, concerns for side-effects in the elderly population are minimal. Donders et al. demonstrated a slight but significant reduction in pain (1.1 and 1.3 points on a visual analog scale at 4 and 12 weeks, respectively) and vestibular redness in women treated with fibroblast lysate [104]. The reduction in pain was more evident in cases of secondary dyspareunia. While topical corticosteroids have been recommended by some providers, the majority of specialists do not find them to be beneficial for vulvodynia. Despite the gathering information linking mast cells and chronic inflammation to vulvodynia, treatments targeting it do not seem to be useful [85]. 8.3. Oral medications The oral use of medication in vulvodynia falls under two main categories: antidepressants and anticonvulsants. Before considering the prescription of drugs belonging to these categories, time must be taken to explain that they are being prescribed for a purpose different from 90

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8.4. Injections

unconditional use of physical therapy [85,120].

There is no good scientific support for the use of injections (steroids, anesthetics or other drugs) in the treatment of vulvodynia. Its effects, if any, are more likely to be noticed in localized vulvodynia (trigger points and painful spots) [85,90]. Isolated or multilevel nerve blocks with a topical anesthetic, with or without a steroid, have shown variable results [113,114]. Data on the use of botulinum toxin A are contradictory: in one uncontrolled study it reduced pain and increased the quality of life and of sexual function for up to 2 years, but in a controlled trial it was no different from placebo [115,116]. Comparison of the findings of these studies is difficult, as different protocols and dosages were used. Mild improvement has been reported with the use of interferon and enoxaparine, but these studies were too small to allow their use to be recommended [85,115,117].

8.7. Surgery Vestibulectomy or other surgical approaches for vulvodynia are the last resort [23]. in the treatment of localized vulvodynia and should be performed only by experienced specialists. One of the most frequently performed procedures is total vestibulectomy, consisting of the excision of the vulvar vestibule, between the hymen (including it) and the line of Hart, and covering of the resulting defect with vaginal mucosa. Some authors have recommended procedures limited to the posterior part of the vestibule, with similar rates of success to total vestibulectomy [122,123], or even just widening procedures [124]. These techniques require less operating time, are associated with better aesthetic results, are technically simpler, and are associated with more rapid postoperative recovery. The surgical approach is one of the few approaches in vulvodynia patients with a fair amount of evidence for effectiveness [85]. The rate of response to these surgical interventions, after proper selection of patients, can be near 90%, with up to 70% having a full response [6]. Women with primary and/or constant vulvodynia are less likely to improve with surgery [125]. The role of surgery for localized vulvodynia is very limited in postmenopausal women, however.

8.5. Psychological interventions Despite the absence of evidence that vulvodynia is a psychological condition, interventions in this field can help the patient or the couple to cope with the distress and the impact of vulvodynia on their relationshiop [6,7]. Interventions such as relaxation techniques, couple therapy, and strategies to help deal with the pain can complement the treatment − sometimes even after successful treatment of the pain. Indeed, even after resolving the objective pain problem, some women will find it difficult to resume sexual activity. The fear avoidance model theorizes that pain can lead to pain-related disability, including catastrophization, rumination and magnification of the pain experience. Cognitive behavioral therapy can be useful in some patients, and despite there being insufficient evidence for its use to be recommended, it has been found to be useful in several studies [85,118,119]. If referral to a mental health professional is considered, the patient must be clearly informed that this is not because the health care provider is considering her problem to be of a psychologic or psychiatric nature [60]. Health care providers treating vulvodynia should work with mental health professionals who fully understand the whole dimension(s) of the condition as well as the needs of the elderly population. The DSM-5 approach to vulvar and sexual pain is likely to be insufficient or even detrimental to vulvodynia patients [13].

8.8. Other approaches Some women may want to try Chinese traditional medicine, acupuncture, or hypnotherapy, as complementary or alternative approaches to conventional treatments [126,127]. The available data, however, do not support their use, even though they do not seem to have a deleterious effect. 9. Conclusions The diagnosis and management of vulvodynia are a clinical challenge in every age group. In postmenopausal women the condition may be erroneously considered to be simply due to low estrogen levels and/ or vulvovaginal atrophy or to the concomitant presence of a vulvar dermatoses. Medical education must focus on this common problem, as most cases are not correctly diagnosed or treated, causing insecurity, suffering, and unnecessary procedures. Older women are more likely to suffer from generalized forms of vulvodynia, often encountering difficult treatment options. The available treatments must be used with special care in older women. Early treatment of the condition, referral to experts, and multidisciplinary teams are recommended.

8.6. Physical therapy and biofeedback Both these approaches have been recommended for the treatment of localized and generalized vulvodynia, especially when there is an associated vaginismus or increased pelvic muscular tone [23,60,77]. It aims to reduce this increased tone, as well as to increase the woman’s awareness of her pelvic floor muscles, in order to control the reflex muscular contractions. As pelvic muscle dysfunction has been described in up to 90% of women with vulvodynia, some authors claim that interventions targeting only the mucosa might be ineffective [63]. However, on the other hand, as long as the painful vestibule is left untreated, many physical therapists cannot achieve good results because the interventions may be too painful for the patient. Treatment options may include manual therapy techniques, pelvic floor muscle and girdle education, biofeedback, dilators, transcutaneous electrical nerve stimulation (TENS), pain physiology education, behavioral and lifestyle modifications to reduce fear/avoidance and catastrophization, peripheral and central nervous system desensitization strategies and home exercise programs [63,120,121]. A recent review by Morin et al. pointed out that most studies show that these procedures are effective in decreasing pain associated with intercourse and lead to an improvement in sexual function. However, and despite the favorable clinical impression, the flaws and elevated risk of bias in these studies do not allow strong recommendations to be made for the

Contributors Pedro Vieira-Baptista and Faustino R. Pérez-López were responsible for the study concept and design. Pedro Vieira-Baptista prepared the initial draft, which was circulated to all other named authors for comments and approval. Conflict of interest The authors declare that they have no conflict of interest. Funding No funding was received for the preparation of this review. Provenance and peer review This article has undergone peer review. 91

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